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Chemical activation of adenylyl cyclase Rv1625c inhibits growth of Mycobacterium tuberculosis on cholesterol and modulates intramacrophage signaling
Author(s) -
Johnson Richard M.,
Bai Guangchun,
DeMott Christopher M.,
Banavali Nilesh K.,
Montague Christine R.,
Moon Caroline,
Shekhtman Alexander,
VanderVen Brian,
McDonough Kathleen A.
Publication year - 2017
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.13701
Subject(s) - adenylyl cyclase , biology , mycobacterium tuberculosis , signal transduction , mycobacterium smegmatis , microbiology and biotechnology , camp dependent pathway , stimulation , tuberculosis , endocrinology , medicine , pathology
Summary Mycobacterium tuberculosis (Mtb) uses a complex 3′, 5′‐cyclic AMP (cAMP) signaling network to sense and respond to changing environments encountered during infection, so perturbation of cAMP signaling might be leveraged to disrupt Mtb pathogenesis. However, understanding of cAMP signaling pathways is hindered by the presence of at least 15 distinct adenylyl cyclases (ACs). Recently, the small molecule V‐58 was shown to inhibit Mtb replication within macrophages and stimulate cAMP production in Mtb. Here we determined that V‐58 rapidly and directly activates Mtb AC Rv1625c to produce high levels of cAMP regardless of the bacterial environment or growth medium. Metabolic inhibition by V‐58 was carbon source dependent in Mtb and did not occur in Mycobacterium smegmatis , suggesting that V‐58‐mediated growth inhibition is due to interference with specific Mtb metabolic pathways rather than a generalized cAMP toxicity. Chemical stimulation of cAMP production by Mtb within macrophages also caused down regulation of TNF‐α production by the macrophages, indicating a complex role for cAMP in Mtb pathogenesis. Together these studies describe a novel approach for targeted stimulation of cAMP production in Mtb, and provide new insights into the myriad roles of cAMP signaling in Mtb, particularly during Mtb's interactions with macrophages.